This proposal will continue the long-standing collaboration with my colleague, Dr. Raymond F. Schinazi. Specifically, his laboratory will evaluate all compounds that we prepare. As interesting leads develop, we will work collaboratively to optimize the antiviral profile of the material. The project will focus on the continued development of practical methodology for the synthesis of purine and pyrimidine nucleoside analogues. Specifically, these studies include the development of methodology for intramolecular 3'- transfer glycosylations, preparing 4'-thianucleosides, selective fluorination of nucleoside analogues, preparing (+)-FDOC in >99%ee and solid-phase, parallel (combinatorial) synthesis of nucleoside analogue libraries. The project will also include the continued synthesis (by the Liotta group) and evaluation (by the Schinazi group) of selected D- and L-nucleoside analogue targets which possess favorable anti-HIV / HBV / HCV _profiles. These include dideoxy purine and pyrimidine nucleoside analogues with an emphasis on fluorinated derivatives, dideoxy, didehydro purine and pyrimidine nucleoside analogs with an emphasis on fluorinated derivatives, heteranucleosides, with particular emphasis on 4'-thianucleosides. Finally, the project will also attempt to develop a rational (de novo) drug design program aimed at the discovery of inhibitors of the RNA-dependent RNA polymerase of hepatitis C.